3-oxygenated 6, 17alpha-dimethylandrostan-17beta-ols



rates 3-OXYGENATED 6,17 a-DIMETHYLANDROSTAN 17 B-OLS John C. Babcock,Portage Township, Kalamazoo County, and J Allan Campbell, Kalamazoo,Mich., assignors to The Upjohn Company, Kalamazoo, Mich, a corporationof Michigan No Drawing. Application February 10, 1958 Serial No. 714,024

7 Claims. (Cl. 260--397.4)

:'"CHa wherein R is selected from the group consisting of keto andfi-hydroxy.

The new compounds of this invention possess anabolic, progestational,antiestrogenic, gonadotropin inhibiting and anti-inflammatory activity.For example, 6,8,l7wdimethylandrostane3fl,l7fi diol possesses higheranti-inflammatory activity than the analogous steroid not methylated atthe 6-position.

Administration of the novel steroids can be in conventional dosage formssuch as pills, tablets, capsules, syrups or elixers for oral use, or inliquid forms which are adaptable to the natural and synthetic corticalsteroid hormones for injectable products.

It is an object of the present invention to provide 3- oxygenated6,17u-dimethylandrostan-l7-ols, particularly6a,17a-dimethyl-l7,8-hydroxyandrostan-3-one, 65,17wdimethyl 1713hydroxyandrostan-S-one, 6a,17a-dimethylandrostane-3fi,17f3-diol, and6,8,17a-dimethylandrostane- 313,17fi-diol. A further object is toprovide processes for the production of6a,l7ot-dimethyl-l7fi-hydroxyandrostan- 3-one,6,8,17ot-dimethyl-17,8hydroxyandrostan-3-one, 6a,l7a-dimethylandrostane-3 8,l7B-diol and 6fl,l7a-dimethylandrostane-3B,17B-diol and 65,17a-dimethylandrostane 3B,l7/i-diol.Other objects of the present invention will be apparent to those skilledin the art to which this invention pertains.

The compounds of the present invention are prepared from6,l7a-dimethyltestosterone by reduction with a reducing agent, forexample with an alkali metal such as sodium or lithium in liquid ammoniaor by catalytic hydrogenation. Using anhydrous liquid ammonia the 4,5-double bond is reduced but not the 3-keto group. Reduction of the 4,5double bond with an alkali metal in liquid atent 0 2,936,312 PatentedMay i0, 196% ammonia in the presence of an alcohol, such as methanol,ethanol, tertiary butyl alcohol, and the like results in concomitantreduction of the 3-keto group to a 3 3- hydroxy group. If desired, theSB-hydroxy group can be oxidized, for example with sodium dichromate ina twophase mixture of methylene chloride and dilute sulfuric acid, orwith chromium trioxide in aqueous acetic acid, to a 3-keto group.Hydrogenation conditions can be chosen to reduce both the 4,5-doublebond and the 3- ketone, as with a platinum catalyst, or solely thedouble bond, as with palladium catalyst. After reduction of the doublebond by means of hydrogen over a palladium catalyst or an alkali metalin anhydrous liquid ammonia the 3-keto group can be further reduced, forexample with lithium aluminum hydride, to a BB-hydroxy group.

In hydrogenation with a palladium catalyst. the catalyst is supported oncharcoal, barium sulfate, zinc oxide, calcium carbonate, and the like.The hydrogenation is usually conducted in a solvent medium. Alkanols,such as methanol, ethanol, tertiary butyl alcohol and the like, hexane,acetone, methyl ethyl ketone, dioxane, acetic acid, ethyl acetate orlike organic solvents may be advantageously employed. The catalyst canbe saturated with hydrogen prior to the introduction of the steroid orpreferably the steroid, catalyst and supporting media can be contactedtogether in a solvent medium prior to introduction of the hydrogen. Itis not necessary to conduct the reaction under pressure, although, whenpressure is utilized, a hydrogen gage pressure of about one to 100pounds or more is operative, a pressure of from about ten to 25 poundsis preferred. Any suitable temperature between about zero and 100degrees centigrade can be employed, with room temperature beingsatisfactory. Hydrogenation is continued until approximately one molarequivalent of hydrogen has been absorbed. The catalyst is then separatedfrom the solution by filtration and the hydrogenated products separatedby conventional separation or extraction procedures such as thoseillustrated in the examples which follow.

When reduction is accomplished with an alkali metal such as, forexample, lithium, sodium, potassium, and the like, with sodium beingpreferred, the reaction is conducted -in liquid ammonia for a period ofa few minutes to about four hours. In addition to the liquid ammonia asolvent such as, for example, ether, tetrahydrofuran, dioxane, ethanoland the like, or mixtures thereof, can be employed if desired using analcohol if reduction of the 3-keto group is desired. On completion ofthe reaction, the reaction mixture is acidified, preferably by additionof ammonium chloride, the ammonia is allowed to evaporate, and theproduct is isolated by conventional procedures such as filtration orextraction with an organic solvent. Purification by chromatography andrecrystallization can be employed if desired.

The following preparations and examples are illustrative of the processand products of the present invention and are not to be construed aslimiting.

PREPARATION 1 613,1 7 11-61 imethyl testosterone To a solution of twograms of 50:,17B-dihYdtOXY-6fi, l7a-dimethylandrostan-3-one [AckroyiAdams, Ellis, Petrow and Stuart-Webb, J. Chem. Soc. 4103 (1957)] in 300milliliters of percent ethanol, under a nitrogen atmosphere, was addedfifteen milliliters of 0.1 normal sodium hydroxide. After 4.5 hours thesolution was neutralized by addition of four drops of glacial aceticacid and then was concentrated to aboutten milliliters by evaporationunder diminished pressure. The resulting mixture was diluted with waterto about thirty milliliters, giving a precipitate which was separated byfiltration, washed with water, dried, and recrystallized from acetone.There was thus obtained 1.33 grams of 6p,17a-dimethyl-testosterone,having a melting point of 160 to 161 degrees centigrade, a rotation [u]of plus 28 degrees in chloroform, an ultraviolet absorption maximum, aof 15,500 at 242.5 millimicrons, and the following analysis:

Anal.Calculated for C H O C, 79.69; H, 10.19. Found: C, 79.15; H, 10.27.

EXAMPLE 1 6 3,1 7oc-dimethyl-1 7 B-hydroxyandrostan3 -one To a solutionof three grams of 613,17 u-dimethyltestosterone in 150 milliliters of 95percent ethanol was added 0.3 gram of five percent palladium oncharcoal. The suspension was shaken with hydrogen under pressure for tenminutes, by which time the theoretical amount of hydrogen had beenabsorbed. The reaction mixture was filtered through diatomaceous earthfilter aid to remove the catalyst and the filtrate was concentrated todryness, dissolved in acetone, and again filtered through diatomaceousearth filter aid. The acetone filtrate was concentrated by evaporationand then was diluted while hot with Skellysolve B hexanes, and cooled togive 1.6 grams of crystals. The thus obtained crystals wererecrystallized from a mixture of acetone and Skellysolve B hexanes togive 65,17u-dimethyl 17,8 hydroxyandrostan 3 one having a melting pointof 168 to 172 degrees centigrade, a rotation [oc] of minus 21 degrees inchloroform and the following analysis:

AnaI.-Calculated for C H O C, 79.19; H, 10.76. Found: C, 78.90; H,10.94.

Alternatively, one gram of 6B,l7a-dimethylandrostane- 3,8,17fl-diol(from Example 2) is dissolved in sixty milliliters of methylene chlorideand a solution of 0.5 gram of sodium dichromate in five milliliters ofdilute sulfuric acid (fifty parts by volume of water to eight parts byvolume of concentrated sulfuric acid) is added. The two phase reactionmixture is stirred seventeen hours at room temperature, then tenmilliliters of methanol is added. After stirring an additional two hoursthe mixture is diluted with water and the aqueous and the methylenechloride phases are separated. The methylene chloride solution is washedwith water, dried over sodium sulfate, and concentrated to dryness,giving a residue. The residue is dissolved in methanol and boiled untilcolorless or nearly so, then is evaporated to dryness giving a residue.The residue is then dissolved in methylene chloride and the solution isfiltered through a diatomaceous earth filter aid. The filtrate isevaporated to dryness leaving a residue which is crystallized from amixture of acetone and Skellysolve B hexanes to give65,17a-dimethyl-17fl-hydroxyandrostan-3-one.

EXAMPLE 2 6 5,1 7a-dimethylandrostane-3 8,1 7,8-diol A solution of onegram of 6,8,17oc-dimethyltestosterone in twelve milliliters of dioxanewas added to a stirred solution of one gram of sodium metal in 150milliliters of liquid ammonia. After one hour six milliliters oftertiary butyl alcohol was added to the reaction mixture. After two morehours the blue color had disappeared, then five grams of ammoniumchloride was added and the ammonia was allowed to evaporate. Theresidual liquid was diluted with water and extracted with ether. Theether extracts were washed with dilute aqueous hydrochloric acid, thenwater, combined, and dried over sodium sulfate. The ether solution wasevaporated to dryness giving a residue which was dissolved in methylenechloride and chromatographed over eighty grams of Florisil syntheticmagnesium silicated. Development of the column with six to eight percentacetone in Skellysolve B hexanes, followed by crystallization from amixture of ethylacetate and Skellysolve B hexanes, gave 0.6 gram of6,8,17a-dimethyl-androstane-3B,17,8-diol, having a melting point of 165to 173 degrees centigrade. This was recrystallized from a mixture ofacetone and Skellysolve B hexanes to obtain an analytical sample of6c,17a-dimethylandrostane-3B,17B- diol having a melting point of 178 to179 degrees centigrade, a rotation [(11 of minus 31 degrees inchloroform and the following analysis:

Anal.Calculated for C H O C, 78.69; H, 11.32. Found: C, 78.74; H, 11.58.

Alternatively, one gram of 65,17a-dimethyl-17B-hy droxyandrostan-3-one(from Example 1) is dissolved in twenty milliliters of benzene and addedslowly, with stirring, to a solution of 0.5 gram of lithium aluminumhydride in milliliters of absolute ether. The reaction mixture isstirred for three hours, then the excess lithium aluminum hydride isdecomposed by cautious addition of ten milliliters of ethyl acetatefollowed by ten milliliters of water. The resulting mixture is filteredand the solvent is removed from the filtrate by evaporation underdiminished pressure, giving a residue. The residue is crystallized froma mixture of acetone and Skellysolve B hexanes giving6B,17a-dimethylandrostanza-36,17B-diol.

EXAMPLE 3 6 0a,] 7u-dimethylandrostane-3 5,1 7fi-di0l In the same manneras given in Example 2, 6a,17adimethyltestosterone [Ackroyd, Adams,Ellis, Petrow and Stuart-Webb, J. Chem. Soc., 4103 (1957)] was treatedwith sodium in liquid ammonia and gave6a,17u-dimethylandrostane-3fl,17fl-diol having a melting point of 208 to209 degrees centigrade and a rotation [0th, of minus nine degrees inchloroform.

EXAMPLE 4 v 6ot,17a-dimethyl-1 7/3-hydroxyandrostan-3-one To a solutionof one gram of 6 x,17a-dimethylandrostane-3,6,l7 3-diol in sixtymilliliters of methylene chloride was added a solution of 0.5 gram ofsodium dichromate in five milliliters of dilute sulfuric acid (fiftyparts by volume of water to eight parts by volume of concentratedsulfuric acid). The two phase reaction mixture was stirred seventeenhours at room temperature, then ten milliliters of methanol was added.After stirring an additional two hours the mixture was diluted withwater and the phases were separated. The methylene chloride phase waswashed with water, dried over sodium sulfate and concentrated todryness, giving a residue. The residue was dissolved in methanol andboiled until loss of color showed that a chromate complex present in thesolution had been destroyed. The methanol solution was evaporated todryness and the residue was dissolved in methylene chloride and filteredthrough a diatomaceous earth filter aid. The filtrate was evaporated todryness and the residue was crystallized from a mixture of acetone andSkellysolve B hexanes giving 0.43 gram of6a,17a-dimethyl-17,8-hydroxyandrostan-3-one having a melting point of178 to 181 degrees centigrade and a rotation [M of plus eight degrees inchloroform.

Alternatively, in the same manner as given in Example 1, treating60L,170c-dl11'16thYltCSiOSt6I'Ol'l6 with hydrogen in the presence of apalladium catalyst is productive of 6a,17a-dimethyl-173-hydroxyandrostan-3-one.

It is to be understood that the invention is not to be limited to theaxact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art. The invention is therefore to be limited only by the scope ofthe appended claims.

We claim:

1. 3 oxygenated 6,170; dimethylandrostan 17B- 6.6a,17a-dimethyl-17p-hydroxyandrostan-3-one. 7.6p,17a-dimethy1-17fi-hydroxyandrostan-3-one.

References Cited in the file of this patent UNITED STATES PATENTSSondheimer et a1 Sept. 18, 1956 Tindall July 29, 1958

1. 3 - OXYGENATED - 6,17A-DIMETHYLANDROSTAN - 17BOL WHEREIN THE3-SUBSTITUENT IS SELECTED FROM THE GROUP CONSISTING OF B-HYDROXY ANDKETO.